Early detection of specific classes of pathogens is accomplished by the innate immune system with help of pattern recognition receptors (PRRs). The detected pathogens include viruses, bacteria, protozoa and fungi, and each constitutively expresses a set of class-specific, mutation-resistant molecules called pathogen-associated molecular patterns (PAMPs).
Toll-like receptors (TLRs) are an important family of PRRs and are widely expressed on innate immune cells, including dendritic cells (DCs), macrophages, mast cells, neutrophils, endothelial cells and fibroblasts. TLRs have broad specificity for conserved molecular patterns shared by bacteria, viruses and parasites.
A number of different TLRs have been characterized. These TLRs bind and become activated by different ligands, which in turn are located on different organisms or structures. The development of immunopotentiator compounds that are capable of eliciting responses in specific TLRs is of interest in the art.
For example, reference I describes certain lipopeptide molecules that are TLR2 agonists. References 2 to 5 each describe classes of small molecule agonists of TLR7. References 6 & 7 describe TLR7 and TLR8 agonists for treatment of diseases. These various compounds include small molecule immunopotentiators (SMIPs).
These compounds have typically been selected for their TLR-modulating activity, without attention to their pharmacokinetic or pharmacodynamic (PK/PD) properties or for their retention at an injection site where they can usefully exert an immunostimulatory effect. The compounds may thus have poor PK/PD or retention profiles when introduced in vivo. Moreover, it may be desirable to modify the systemic exposure of the compounds e.g. to minimise potential systemic side effects in widespread prophylactic immunisations, or to maintain systemic exposure in an emergency immunotherapeutic setting. As shown in FIGS. 1 to 5, injection of a TLR7 active SMIP into a subject initially results in high serum concentration which quickly drops, and injected compounds can be fully cleared from muscle within 24 hours.
It is an object of the invention to provide new formulations of immunopotentiators, and in particular of SMIPs, which can modify or improve the immunopotentiators' pharmacological properties, such as PK/PD profiles, cellular uptake, retention at injection sites, reduced general activation of B cells, etc. It is a further object to provide formulations which can improve their immunostimulating activity